Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. As a significant public health problem because of its known association with the Gateway theory of drug abuse, NIDA's mission over the past few years has been aimed at identifying safe and effective candidate therapies for marihuana abuse and dependence, particularly those that can be given to vulnerable populations. The overall objectives of this proposal are to test a nutritional supplement of the natural brain chemical, cytidine-5'-diphosphate choline (citicoline) for its effects on marihuana-induced intoxication and abuse patterns. This supplement was recently shown to reduce marihuana use in an open label trial of a grant that was awarded under RFA-DA-04-014 (Medication Development for Cannabis-Related Disorders). Because citicoline is a natural chemical in mammalian brain, it is relatively safe and has been very useful in treating stroke and other neurological disorders. It is still unclear how marihuana affects brain function, either acutely or after chronic use, so the proposed studies are designed to collect data that will serve as a foundation for exploring new strategies for treating marihuana abuse. These goals will be accomplished by using brain imaging techniques such as electroencephalography, magnetic resonance imaging and studies will be conducted to identify the mechanism of action of citicoline's effects on marihuana use and its intoxicating effects. As a first step in devising a medication to treat marihuana dependence we propose to conduct a double-blind, placebo-controlled assessment of citicoline on marihuana use patterns in a natural setting. We will then document the effects of acutely administered marihuana on regional cerebral blood flow using BOLD signal detection. Finally, we will study whether citicoline alters marihuana-induced cue-induced craving. Collectively, these studies should yield important information on how supplementation with a natural brain chemical alters marihuana's effects such that its use is decreased. The results of the present series of studies could have important implications for the pharmacotherapy of marihuana dependence as well as primary and secondary prevention of the neurobiological damage associated with chronic use. Furthermore, the outcome of the proposed project could offer important insights into the pathophysiology and course of marihuana dependence (and potentially on other drug dependence disorders). Lastly, given the lack of any side effects of citicoline, these results also may provide important leads for expanding the relatively limited treatment options for vulnerable populations such as pregnant women, children born to drug-dependent mothers and adolescents. PUBLIC HEALTH RELEVANCE: Marihuana is the most commonly abused illegal drug in the United States, yet there are no treatments for its abuse or dependence. Citicoline, a naturally occurring chemical in the brain, has been shown to reduce marihuana use in a pilot clinical trial. Using magnetic resonance brain imaging and EEG techniques, this application will explore the mechanism of action and develop new treatment strategies for marihuana dependence.